Certain conditions, such as bypass surgery, trauma, head injuries, emboli, septic shock, pneumonia, smoke inhalation and premature birth, can result in lung edema and impaired alveolar gas exchange. In such patients, the use of elevated levels of inhaled oxygen is necessary to achieve acceptable blood oxygen saturation. However, prolonged exposure to greater than 0.5 atmospheres of oxygen can result in lung injury, edema, fibrosis, and, eventually death. Methods for inhibiting the toxic effects of such elevated levels of inhaled oxygen are, therefore, desirable.
Results from investigations with laboratory animals have led to a three phase hypothesis for the pathogenesis of pulmonary oxygen toxicity. During the first or initiation phase (24 to 48 hours at 1 atmosphere of inhaled oxygen), reactive oxygen radicals are generated within alveolar cells causing endothelial lactate dehydrogenase (LDH) release, macrophage release of a neutrophil chemotactic factor, epithelial damage, very mild extravascular leakage of fluid and chest stiffness. The second, amplification or inflammation, phase (72 to 96 hours at 1 atmosphere of inhaled oxygen) is characterized by a massive neutrophil infiltration, marked endothelial, epithelial and surfactant damage, moderate pulmonary edema, and mild to moderate respiratory distress or "ill feeling". During the third or destructive phase, these effects resolve within additional days (1 to 7) in death or within months (1 to 3) in pulmonary fibrosis. See, e.g., Crapo, J. D., Ann. Rev. Physiol. 48: 721 (1986).
Certain cytotoxic agents have been shown to reduce circulating and tissue neutrophils. These cytotoxic agents, however, cannot be used as therapies in humans. Furthermore, reducing circulating and tissue neutrophils does not necessarily prevent lung injury due to hypoxia. For example, Shasby et al, J. Appl. Physiol. 52:1237-1244 (1982) describe findings using nitrogen mustard that suggest that granulocytes may contribute to production of edema in acute oxygen toxicity. Suttrop et al, J. Clin. Invest. 70:342-350 (1982), describe findings using SOD, inter alia, that indicate that the increase in susceptibility of lung cells to neutrophil-mediated oxidant damage is an effect of hyperoxia on lung cells. Parrish et al, J. Clin. Invest. 74:956-965 (1984), describe early accumulation of neutrophils in oxygen toxicity, particularly in C5-sufficient mice. Krieger et al, J. Appl. Physiol. 58:1326-1330 (1985), describe findings suggesting that the synergistic interaction between hyperoxia and granulocytes in producing acute lung injury involves a primary effect of hyperoxia on the lung itself. Laughlin et al, J. Appl. Physiol. 61:1126-1131 (1986), concluded that neutrophils do not play a significant role during the early stages of sublethal hyperoxic injury to rabbit alveolar epithelium. Smith et al, J. Lab Clin. Med. 111(4): 449-458(1988), describe results indicating that PMNs are not required for either the development or progression of hyperoxic lung damage in mice. Das et al, Biomed. Biochim. Acta 47(12):1023-1036 (1988), describe a study demonstrating that ibuprofen cannot prevent hyperoxic lung injury although it inhibits the influx of PMN into the injured lung, suggesting that PMN are not directly involved in the injury process.
Neutrophils are one group of white blood cells whose diapedesis is controlled by cellular adhesion. Cellular adhesion is a process through which leukocytes attach to cellular substrates, such as endothelial cells, in order to migrate from circulation to sites of ongoing inflammation, and properly defend the host against foreign invaders such as bacteria or viruses. An excellent review of the defense system is provided by Eisen, H. W., (In: Macrobiology, 3rd Ed., Harper & Row, Philadelphia, pA (1980), pp. 290-295 and 381-418).
One of the molecules on the surface of endothelial cells which participates in the adhesion process is the intercellular adhesion molecule ICAM-1. See Rothlein et al, J. Immunol. 137:1270 (1986), (hereinafter referred to as ("Rothlein et al"). This molecule has been shown to mediate adhesion by binding to molecules of the CD18 family of glycoproteins which are present on the cell surfaces of leukocytes (Sanchez-Madrid, F. et al., J. Exper. Med 158:1785-1803 (1983); Keizer, G. D. et al., Eur. J. Immunol. 15:1142-1147 (1985)). This glycoprotein family is composed of heterodimers having one alpha chain (also referred to as "CD11") and one beta chain (also referred to as "CD18"). There are three major members of the CD18 family: p150,95, Mac-1 and LFA-1. Mac-1 is a heterodimer found primarily on macrophages, granulocytes and large granular lymphocytes. LFA-1 is a heterodimer found on most lymphocytes (Springer, T. A., et al. Immunol. Rev. 68:111-135 (1982)). p150,95 has a tissue distribution similar to Mac-1, and also plays a role in cellular adhesion (Keizer, G. et al., Eur. J. Immunol. 15:1142-1147 (1985)).
Mouse monoclonal antibodies to human ICAM-1 have been shown to inhibit lymphocyte proliferative responses requiring cell/cell interactions as well as inhibiting granulocyte attachment and subsequent migration through endothelial cell monolayers in vitro. Anti-ICAM-1 antibodies are also known to inhibit leukocyte migration to inflamed lungs in rabbits, kidney allograft rejection and antigen-induced airway hyperreactivity in primates. See, e.g., Dustin et al J. Immunol. 137:245 (1986) Barton et al, J. Immunol. 143:1278 (1989), Cosimi et al., J. Immunol. 144:4604 (1990) and Wegner et al, Science 247:456 (1990).
Anti-CD18 antibodies have been described as useful in treating hemorrhagic shock in rabbits. Vedder et al, J. Clin, Invest. 81: 939 (1988). Anti-CD18 antibodies have been shown not to increase susceptibility to sepsis when used to inhibit neutrophil adherence in rabbits. Mileski et al, Surgical Forum, Infection and its Mediators, p. 107 (1989).
Accordingly, it is the purpose of this invention to provide a novel method for inhibiting pulmonary oxygen toxicity in a patient requiring elevated levels of inhaled oxygen, using an adhesion molecule or antibody thereto.